Fasting induces hepatic lipid accumulation by stimulating peroxisomal dicarboxylic acid oxidation.

Content Provider	Europe PMC
Author	Zhang, Xiao Gao, Ting Deng, Senwen Shang, Lin Chen, Xiaocui Chen, Kai Li, Ping Cui, Xiaojuan Zeng, Jia
Copyright Year	2021
Abstract	Fasting induces lipid accumulation in the liver, while the mechanisms by which fasting dysregulates liver fatty acid oxidation are not clear. Fatty acid ω-oxidation is induced in the fasting state, and administration of dicarboxylic acids to fasting animals decreases plasma ketone bodies. We hypothesized that endogenous dicarboxylic acids might play a role in controlling mitochondrial β-oxidation in fasting animals. A peroxisome proliferator-activated receptor-alpha agonist and an inhibitor for peroxisomal β-oxidation were administered to the fasting rats to investigate the role of dicarboxylic acids in liver fatty acid oxidation and lipid homeostasis. We observed that excessive β-oxidation of endogenous dicarboxylic acids by peroxisomes generated considerable levels of succinate in the liver. Excessive succinate oxidation subsequently increased the mitochondrial NADH/NAD+ ratio and led to an accumulation of 3-OH-CoA and 2-enoyl-CoA intermediates in the liver. This further induced feedback suppression of mitochondrial β-oxidation and promoted hepatic lipid deposition and steatosis. Specific inhibition of peroxisomal β-oxidation attenuated fasting-induced lipid deposition in the liver by reducing succinate production and enhancing mitochondrial fatty acid oxidation. We conclude that suppression of mitochondrial β-oxidation by oxidation of dicarboxylic acids serves as a mechanism for fasting-induced hepatic lipid accumulation and identifies cross talk between peroxisomal and mitochondrial fatty acid oxidation.
ISSN	00219258
Volume Number	296
PubMed Central reference number	PMC8102918
PubMed reference number	33811861
Journal	The Journal of Biological Chemistry [J. Biol. Chem]
e-ISSN	1083351X
DOI	10.1016/j.jbc.2021.100622
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2021-01-01
Access Restriction	Open
Rights License	This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). © 2021 The Authors
Subject Keyword	fatty acid oxidation ketogenesis peroxisome dicarboxylic acid peroxisome proliferator activator receptor α 3-OH-CoA, 3-hydroxyacyl-CoA ABCD1, peroxisomal ATP-binding cassette transporter D AcAc, acetoacetate ACS, acyl-CoA synthetase ACOX1, acyl-CoA oxidase-1 βOHB, β-hydroxybutyrate C12, laurate C12-CoA, CoA thioester of laurate CFB, clofibrate CPT1, carnitine palmitoyltransferase-1 DCA, dicarboxylic acid DCA12, decanedicarboxylic acid DC12-CoA, mono-CoA thioester of decanedicarboxylic acid FFA, free fatty acid KB, ketone body L-BP, L-bifunctional protein LC-acyl-CoA, long-chain acyl-CoA LCAD, long-chain acyl-CoA dehydrogenase LCADH, long-chain alcohol dehydrogenase MCAD, medium-chain acyl-CoA dehydrogenase NAFLD, nonalcoholic fatty liver disease PPARα, peroxisome proliferator activator receptor α isoform TAG, triacylglyceride TBARS, thiobarbituric acid reactive substances TDYA, 10,12-tricosadiynoic acid thiolase, peroxisomal 3-oxoacyl-CoA thiolase
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology Biochemistry